Balloon dilatation of the coronary arteries is a critically important modality in treating patients suffering from angina due to coronary artery disease. Although the initial success of dilating the coronary artery is over 90%, restenosis occurs in 25 to 50% of patients weeks or months later. It is now known that restenosis is due to activation of smooth muscle cells (SMC) that normally reside in the arterial wall; after balloon injury they proliferate and migrate to the subintema, thereby obstructing blood flow. We are attempting to develop novel approaches, based on the molecular response to injury, to prevent restenosis. For one approach, we are using antisense, olygodyoxinucliatides (ODNS) in an effort to selectively inhibit specific growth factors that cause SMC proliferation. Proteins are synthesized by translation of mRNA. The latter consists of a series of nucleotides which encode a message designating a specific protein. This is called the "sense" message. The sequence of nucleotides that are the exact complement of the sense mRNA is called "antisense"--it does not encode any message that can be translated into a protein. The antisense sequence binds to the sense mRNA making it impossible for the mRNA to be translated into -its protein. Using a model of quiescent rat aortic SMC, which can be induced to proliferate in response to serum or growth factors, we are testing ODNs targeted to proliferating cell nuclear antigen (PCNA), a 36kDa nuclear protein expressed at high levels only when cells are rapidly proliferating. PCNA is a prerequisite for the induction of DNA replication. Our preliminary results have demonstrated that proliferating rat SMC are growth-inhibited by exogenously added ODNs targeted to rat PCNA in a dose-dependent fashion. Maximal inhibition is 50%. ODNs target understanding of the mechanisms responsible for SMC proliferation; it may also provide new molecules to treat the clinical problem of restenosis.